Proteolytic Activation of Human Cathepsin A
Open accessAbstract
Galactosialidosis is a human lysosomal storage disease caused by deficiency in the multifunctional lysosomal protease cathepsin A (also known as protective protein/cathepsin A, PPCA, catA, HPP, and CTSA; EC 3.4.16.5). Previous structural work on the inactive precursor human cathepsin A (zymogen) led to a two-stage model for activation, where proteolysis of a 1.6-kDa excision peptide is followed by a conformational change in a blocking peptide occluding the active site. Here we present evidence for an alternate model of activation of human cathepsin A, needing only cleavage of a 3.3-kDa excision peptide to yield full enzymatic activity, with no conformational change required. We present x-ray crystallographic, mass spectrometric, amino acid sequencing, enzymatic, and cellular data to support the cleavage-only activation model. The results clarify a longstanding question about the mechanism of cathepsin A activation and point to new avenues for the design of mechanism-based inhibitors of the enzyme.
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Cathepsin A is synthesized as an inactive precursor and undergoes proteolytic maturation in acidic lysosomes.
“Cathepsin A is synthesized as an inactive precursor and undergoes proteolytic maturation in acidic lysosomes 32 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [32]
The Discussion states that cathepsin A is processed from an inactive zymogen into an active mature protease, and the Results report proteolytic processing in human cells (pages unavailable in our copy). The paper describes lysosomal activity and activity at acidic pH, but the passages do not establish that maturation occurs specifically in acidic lysosomes. (LLM, conf=0.84)
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- [1]1. d'Azzo, A. ∙ Andria, G. ∙ Strisciuglio, P. ... Scriver, C.R. ∙ Beaudet, A.L. ∙ Sly, W.S. ... (Editors) The Metabolic and Molecular Bases of Inherited Disease McGraw-Hill, New York, 2001; 3811-3826 Google Scholar
- [2]2. van der Spoel, A. ∙ Bonten, E. ∙ d'Azzo, A. Role of protective protein cathepsin A in the activation of lysosomal neuraminidase Am. J. Hum. Genet. 1997; 61:A27 Google Scholar
- [3]3. van der Spoel, A. ∙ Bonten, E. ∙ d'Azzo, A. Transport of human lysosomal neuraminidase to mature lysosomes requires protective protein/cathepsin A EMBO J. 1998; 17:1588-1597 Crossref Scopus (113) PubMed Google Scholar
- [4]4. Bonten, E.J. ∙ d'Azzo, A. Lysosomal neuraminidase: catalytic activation in insect cells is controlled by the protective protein/cathepsin A J. Biol. Chem. 2000; 275:37657-37663 Full Text Full Text (PDF) Scopus (47) PubMed Google Scholar
- [5]5. Hiraiwa, M. Cathepsin A/protective protein: an unusual lysosomal multifunctional protein Cell Mol. Life Sci. 1999; 56:894-907 Crossref Scopus (77) PubMed Google Scholar
- [6]6. Morreau, H. ∙ Galjart, N.J. ∙ Willemsen, R. ... Human lysosomal protective protein: glycosylation, intracellular transport, and association with β-galactosidase in the endoplasmic reticulum J. Biol. Chem. 1992; 267:17949-17956
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- Authors
- Kolli, N., & Garman, S. C.
- Affiliations
- University of Massachusetts Amherst (US)
- Corresponding author
- Garman, Scott C.
- ORCID
- Garman, Scott C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 289
- Issue
- 17
- Pages
- 11592-11600
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4002070
- OpenAlex
- W2026163413
- Cited by
- 30
- References
- 0
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1
- FWCI
- 0.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 DK76877, RR-15301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- cathepsin A, proteolytic activation, zymogen activation, galactosialidosis, lysosomal storage disease, blocking peptides, conformational change, mechanism-based inhibitors, lysosomal proteases, active site
- MeSH terms
- Electrophoresis, Polyacrylamide Gel, Enzyme Activation, Humans, Models, Molecular, Protein Conformation, Cathepsin A, Proteolysis
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